title: Substance P regulates Ih via a NK-1 receptor in vagal sensory neurons of the ferret.
abstract: Substance P (SP) hyperpolarizes approximately 80% of ferret vagal sensory neurons (nodose ganglion neurons) via NK-1 receptor-mediated activation of a potassium current (IK). A depolarizing current activated by membrane hyperpolarization could minimize the SP-induced hyperpolarization. Such a current exists in 65% of the nodose neurons (n = 264). In this study, we examine this current and how it can interact with SP-induced membrane hyperpolarizations. This slowly developing, noninactivating inward current, designated Ih, was activated maximally at about -120 mV and had a reversal potential value of -23 +/- 4.4 mV (n = 4). The time course of activation followed voltage-dependent, monoexponential kinetics. Steady-state activation curves derived from tail current analysis were well fit by a Boltzmann equation yielding a half-activation potential (V1/2) of-77 +/- 1.5 mV and a ks value of 18 +/- 0.5 (n = 8). In the presence of 1 mM cesium, the current was completely abolished. These parameters are consistent with those derived for Ih in other neurons. Substance P (200 nM) reduced the magnitude of Ih elicited by membrane hyperpolarizations to about -110 mV but did not affect the magnitude of Ih elicited by hyperpolarizations to more negative potentials. Tail current analysis revealed that this effect was the result of a SP-induced shift of the Ih activation curve to more negative membrane potentials. The V1/2 value for Ih was shifted by -20 +/- 1.4 mV in the presence of SP with no change in ks (18 +/- 0.7; n = 5). The SP effect on Ih, like its effect on IK, was blocked reversibly by 10 nM CP99,994, a NK-1 antagonist, and was mimicked by the NK-1 agonist Ac-[Arg6, Sar9, Met(O2)11]SP(6-11) (ASMSP; 200 nM). Ih was not affected by NK-2 or NK-3 selective agonists (n = 4 for each) nor was the effect of SP on Ih reduced by an NK-2 antagonist (n = 4). These results show that SP activates a NK-1 receptor coupled to the Ih channel. Thus NK-1 receptor activation in ferret vagal afferents not only leads to membrane hyperpolarization but it also can enhance synergistically this inhibitory effect by decreasing Ih.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore, Maryland 21201-1559, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Jafri
authors.forename: D
authors.initials: D
authors.lastname: Weinreich
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002412:Cations / Q000378:metabolism; D005289:Ferrets; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000494:pharmacology*; D014630:Vagus Nerve / Q000166:cytology / Q000187:drug effects*
chemical_list: D001549:Benzamides; D002412:Cations; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; C073839:SR 48968